The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

Predisposing and triggering factors of large-scale landslides in Debre Sina area, central Ethiopian highlands

A large number of landslide events have repeatedly struck the border zone of the northwestern plateaus of Ethiopia. Debre Sina area is one of the most tectonically active areas located along the western margin of the Afar depression, which is frequently affected by landslides. Despite that, urban and rural development is currently active in almost the entire area. It is crucial, therefore, to understand the main causes and failure mechanisms of landslides in the Debre Sina area and its surroundings. The present study investigated landslides using field mapping of geological and geomorphological features, remote sensing, geo-morphometric analysis, structural analysis, rainfall data, landslide inventory, and earthquake data. The results of the study indicate that large-scale and deep-seated landslide problems appear to be caused by complex geological settings and rugged topography. In particular, the location and morphology of the Yizaba Wein and Shotel Amba landslides are strongly controlled by geological structures. Their flanks are bounded by high angle faults, and their main basal failure surfaces have developed within a W–E striking eastward-dipping normal fault zone. The complex litho-structural and morphologic settings play a vital role in controlling the geometry of the slip surfaces and the stability of the landslides

Monitoring nitrate reduction: hydrogeochemistry and clogging potential in raw water wells.

The mainly agricultural input of NO3- and compliance with drinking water guideline values pose major challenges for many water suppliers. Additionally, associated changes in hydrochemistry, especially concerning products of NO3- reduction (Fe2+/3+, Mn2+/4+, Ca2+, Mg2+, SO42-, HCO3-) and subsequent reactions, can have a major influence on mineral saturation states and well yield: well productivity can be strongly reduced by mineral precipitation and silting. To evaluate hydrogeochemical evolution and clogging potential for a given well field, thorough hydrochemical and geochemical investigations are required. Therefore, time-dependent and depth-specific ion concentrations in water samples (n = 818) were analysed in a catchment area of a waterworks in western Germany. The sediments of the aquifers were extensively investigated for their geochemistry (CS, scanning electron microscope, aqua regia digestion and dithionite solution; n = 253). In addition, PhreeqC was used to model saturation indices in order to identify possible mineral precipitation in the wells. Results show a high NO3- input into deep wells screened in Tertiary sediments due to an admixture of Quaternary groundwater. Directly at the Quaternary-Tertiary boundary, chemolithotrophic NO3- reduction consuming pyrite occurs. Protons released during the process are pH-buffered by dissolving carbonate minerals. Overall, the hydrochemistry and especially the saturation indices are strongly influenced by NO3- reduction and its degradation products. A change in well yield has not yet been observed, but future clogging by ochre formation or sintering cannot be excluded

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

The effect of hydrogeological and hydrochemical dynamics on landslide triggering in the central highlands of Ethiopia

The volcanic terrain at the western margin of the Main Ethiopian Rift in the Debre Sina area is known for its slope stability problems. This report describes research on the effects of the hydrogeological and hydrochemical dynamics on landslide triggering by using converging evidence from geological, geomorphological, geophysical, hydrogeochemical and isotopic investigations. The chemical characterization indicates that shallow to intermediate aquifers cause groundwater flow into the landslide mass, influencing long-term groundwater-level fluctuations underneath the landslide and, as a consequence, its stability. The low content of total dissolved solids and the bicarbonate types (Ca–Mg–HCO3 and Ca–HCO3) of the groundwater, and the dominantly depleted isotopic signature, indicate a fast groundwater flow regime that receives a high amount of precipitation. The main causes of the landslide are the steep slope topography and the pressure formed during precipitation, which leads to an increased weight of the loose and weathered materials. The geophysical data indicate that the area is covered by unconsolidated sediments and highly decomposed and weak volcanic rocks, which are susceptible to sliding when they get moist. The heterogeneity of the geological materials and the presence of impermeable layers embodied within the highly permeable volcanic rocks can result in the build-up of hydrostatic pressure at their interface, which can trigger landslides. Intense fracturing in the tilted basalt and ignimbrite beds can also accelerate infiltration of water, resulting to the build-up of high hydrostatic pressure causing low effective normal stress in the rock mass, giving rise to landslides

Routine Left Ventricular Pacing for Patients Undergoing Transcatheter Aortic Valve Replacement

ABSTRACTBackground: Rapid ventricular pacing is often required during transcatheter aortic valve replacement (TAVR) procedures. Pacing via the retrograde left ventricular guidewire (LV-GW) is an al..

Cardiovascular magnetic resonance by non contrast T1-mapping allows assessment of severity of injury in acute myocardial infarction

BACKGROUND: Current cardiovascular magnetic resonance (CMR) methods, such as late gadolinium enhancement (LGE) and oedema imaging (T2W) used to depict myocardial ischemia, have limitations. Novel quantitative T1-mapping techniques have the potential to further characterize the components of ischemic injury. In patients with myocardial infarction (MI) we sought to investigate whether state-of the art pre-contrast T1-mapping (1) detects acute myocardial injury, (2) allows for quantification of the severity of damage when compared to standard techniques such as LGE and T2W, and (3) has the ability to predict long term functional recovery. METHODS: 3T CMR including T2W, T1-mapping and LGE was performed in 41 patients [of these, 78% were ST elevation MI (STEMI)] with acute MI at 12-48 hour after chest pain onset and at 6 months (6M). Patients with STEMI underwent primary PCI prior to CMR. Assessment of acute regional wall motion abnormalities, acute segmental damaged fraction by T2W and LGE and mean segmental T1 values was performed on matching short axis slices. LGE and improvement in regional wall motion at 6M were also obtained. RESULTS: We found that the variability of T1 measurements was significantly lower compared to T2W and that, while the diagnostic performance of acute T1-mapping for detecting myocardial injury was at least as good as that of T2W-CMR in STEMI patients, it was superior to T2W imaging in NSTEMI. There was a significant relationship between the segmental damaged fraction assessed by either by LGE or T2W, and mean segmental T1 values (P < 0.01). The index of salvaged myocardium derived by acute T1-mapping and 6M LGE was not different to the one derived from T2W (P = 0.88). Furthermore, the likelihood of improvement of segmental function at 6M decreased progressively as acute T1 values increased (P < 0.0004). CONCLUSIONS: In acute MI, pre-contrast T1-mapping allows assessment of the extent of myocardial damage. T1-mapping might become an important complementary technique to LGE and T2W for identification of reversible myocardial injury and prediction of functional recovery in acute MI